title: Inhibitory effect of α-lipoic acid on platelet aggregation is mediated by PPARs.
abstract: Peroxisome proliferator-activated receptors (PPARs) isoforms (α, β/δ, and γ are present in human platelets, and activation of PPARs inhibits platelet aggregation. α-Lipoic acid (ALA), occurring naturally in human food, has been reported to exhibit an antiplatelet activity. However, the mechanisms underlying ALA-mediated inhibition of platelet aggregation remain unknown. The aim of this study was to investigate whether the antiplatelet activity of ALA is mediated by PPARs. ALA itself significantly induced PPARα/γ activation in platelets and increased intracellular amounts of PPARα/γ by blocking PPARα/γ secretion from arachidonic acid (AA)-activated platelets. Moreover, ALA significantly inhibited AA-induced platelet aggregation, Ca(2+) mobilization, and cyclooxygenase-1 (COX-1) activity, but increased cyclic AMP production in rabbit washed platelets. Importantly, ALA also enhanced interaction of PPARα/γ with protein kinase Cα (PKCα) and COX-1 accompanied by an inhibition of PKCα activity in resting and AA-activated platelets. However, the above effects of ALA on platelets were markedly reversed by simultaneous addition of selective PPARα antagonist (GW6471) or PPARγ antagonist (GW9662). Taken together, the present study provides a novel mechanism by which ALA inhibition of platelet aggregation is mediated by PPARα/γ-dependent processes, which involve interaction with PKCα and COX-1, increase of cyclic AMP formation, and inhibition of intracellular Ca(2+) mobilization.
authors.affiliation: Department of Physiology, National Defense Medical Center, Taipei, Taiwan. tcchou@ms5.hinet.net
authors.forename: Tz-Chong
authors.initials: TC
authors.lastname: Chou
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Shih
authors.forename: Ying-Tsung
authors.initials: YT
authors.lastname: Chen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood; D051545:Cyclooxygenase 1 / Q000097:blood; D047493:PPAR alpha / Q000097:blood / Q000187:drug effects*; D047495:PPAR gamma / Q000097:blood / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000097:blood; D011817:Rabbits; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D047493:PPAR alpha; D047495:PPAR gamma; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D008063:Thioctic Acid; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051571:Protein Kinase C-alpha